Nature Communications (Feb 2024)

Mutation-specific CAR T cells as precision therapy for IGLV3-21R110 expressing high-risk chronic lymphocytic leukemia

  • Florian Märkl,
  • Christoph Schultheiß,
  • Murtaza Ali,
  • Shih-Shih Chen,
  • Marina Zintchenko,
  • Lukas Egli,
  • Juliane Mietz,
  • Obinna Chijioke,
  • Lisa Paschold,
  • Sebastijan Spajic,
  • Anne Holtermann,
  • Janina Dörr,
  • Sophia Stock,
  • Andreas Zingg,
  • Heinz Läubli,
  • Ignazio Piseddu,
  • David Anz,
  • Marcus Dühren-von Minden,
  • Tianjiao Zhang,
  • Thomas Nerreter,
  • Michael Hudecek,
  • Susana Minguet,
  • Nicholas Chiorazzi,
  • Sebastian Kobold,
  • Mascha Binder

DOI
https://doi.org/10.1038/s41467-024-45378-w
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 14

Abstract

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Abstract The concept of precision cell therapy targeting tumor-specific mutations is appealing but requires surface-exposed neoepitopes, which is a rarity in cancer. B cell receptors (BCR) of mature lymphoid malignancies are exceptional in that they harbor tumor-specific-stereotyped sequences in the form of point mutations that drive self-engagement of the BCR and autologous signaling. Here, we use a BCR light chain neoepitope defined by a characteristic point mutation (IGLV3-21R110) for selective targeting of a poor-risk subset of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR) T cells. We develop murine and humanized CAR constructs expressed in T cells from healthy donors and CLL patients that eradicate IGLV3-21R110 expressing cell lines and primary CLL cells, but neither cells expressing the non-pathogenic IGLV3-21G110 light chain nor polyclonal healthy B cells. In vivo experiments confirm epitope-selective cytolysis in xenograft models in female mice using engrafted IGLV3-21R110 expressing cell lines or primary CLL cells. We further demonstrate in two humanized mouse models lack of cytotoxicity towards human B cells. These data provide the basis for advanced approaches of resistance-preventive and biomarker-guided cellular targeting of functionally relevant lymphoma driver mutations sparing normal B cells.